4.1. Therapeutic indications

Isoniazid 100 mg Tablets are indicated for the treatment of all forms of pulmonary and extra-pulmonary tuberculosis.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2. Posology and method of administration

Official guidance should always be consulted when selecting the dose regimens to be used for adults and children (according to age and body weight), the duration of therapy and the total content of the combination treatment regimen.

Posology:

Adults:

The dose of isoniazid for the treatment of tuberculosis is commonly 4 to 5 mg per kilogram bodyweight daily given by mouth in single or divided doses up to a maximum of 300 mg daily. Up to 10 mg per kilogram body-weight daily may be given particularly during the first 1 to 2 weeks of treatment of tuberculous meningitis. A dose of 15 mg per kilogram has been given two or three times weekly in intermittent treatment regimens.

Elderly:

No dosage reduction is necessary in the elderly, but caution should be exercised due to the possible decrease in renal and hepatic function.

Paediatric population:

The usual daily dose for children aged three months and above is from 10 up to 15mg per kilogram body-weight daily in single or divided doses.

Isoniazid should not be used in children aged 0 to 3 months because of the lack of specific data.

Method of administration:

Isoniazid 100 mg tablets should be taken preferably on an empty stomach, i.e. at least 30 minutes before a meal or 2 hours after a meal. Tablets must be swallowed whole and not chewed.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Previous experience of severe adverse reaction to Isoniazid including drug induced liver disease (See section 4.4).

4.4. Special warnings and precautions for use

All patients should have baseline liver function tests performed and repeated at regular intervals during treatment. If serum AST rises to more than three times normal, or there is any increase in bilirubin, treatment should be withdrawn. Special precautions are required in patients with impaired liver function. Any deterioration in liver function in these patients is an indication for stopping treatment.

Isoniazid should not be given to patients who have experience severe adverse reactions including drug-induced liver disease. Care should be taken in giving isoniazid to patients suffering from convulsive disorders, diabetes mellitus, chronic alcoholism, or impaired liver or kidney function or to patients taking other potentially hepatoxic agents. If symptoms of hepatitis such as malaise, fatigue, anorexia, and nausea develop isoniazid should be discontinued immediately.

Isoniazid should be used with caution in patients with a history of psychosis.

Advanced age, female gender, slow acetylators, malnutrition, HIV infection, preexisting liver disease, and extra-pulmonary tuberculosis were identified as risk factors for isoniazid-induced hepatotoxicity.

Patients who are at risk of neuropathy or pyridoxine deficiency, including those who are diabetic, alcoholic, malnourished, uraemic, pregnant, or infected with HIV, should be given pyridoxine.

4.5. Interaction with other medicinal products and other forms of interaction

When isoniazid is given to patients who inactivate it slowly or to patients receiving paraminosalicyclic acid concurrently, tissue concentrations may be enhanced and adverse effects are more likely to appear. There may be an increased risk of liver damage in patients receiving rifampicin and isoniazid but liver enzymes are raised only transiently.

Concurrent use of other hepatotoxic medications with isoniazid may increase the potential for hepatotoxicity.

Isoniazid can inhibit the hepatic metabolism of a number of drugs, in some cases leading to increased toxicity. These include the antiepileptics carbamazepine, primidone, and phenytoin, the benzodiazepines diazepam and triazolam, chlorzoxazone, and disulfiram. Concomitant benzodiazepine (diazepam, triazolam) and isoniazid therapy has been reported to result in an increased risk of benzodiazepine toxicity (sedation, respiratory depression).

Isoniazid has been reported to cause substantial elevations of serum concentrations of carbamazepine and symptoms of carbamazepine toxicity at isoniazid doses of 200 mg daily or more. The concurrent used is not recommended unless the effects can be closely monitored and suitable downward dosage adjustments made (a reduction between one-half or one-third was reported effective).

Phenytoin dosage adjustment maybe necessary during and after isoniazid therapy especially in slow acetylators of isoniazid.

Isoniazid may increase renal excretion of pyridoxine; requirements for pyridoxine may be increased in patients receiving isoniazid concurrently. Concurrent use of isoniazid may reduce the metabolism of theophylline, increasing theophylline plasma concentrations. Propranolol has been reported to cause a significant reduction in the clearance of concurrently administered isoniazid. Concurrent use of cycloserine with isoniazid results in increased incidence of central nervous system effects such as dizziness or drowsiness, dosage adjustment may be necessary and patients should be monitored closely for signs or central nervous system toxicity especially if performing tasks requiring alertness.

Isoniazid may reduce the therapeutic effects of levodopa.

Concomitant administration of isoniazid with itraconazole may result in significant decreases in itraconazole serum concentrations and therapeutic failure. Co-administration is not recommended. Isoniazid may decrease ketoconazole serum levels. Concurrent use should be well monitored and dosage increases made if necessary.

Because the clearance of isoniazid was found doubled when zalcitabine was given in HIV positive patients, concurrent use of isoniazid and zalcitabine should be monitored to ensure isoniazid effectiveness.

There may be an increased risk of distal sensory neuropathy when isoniazid is used in patients taking stavudine (d4T).

Concurrent use of isoniazid with other neurotoxic medication may produce additive neurotoxicity.

Isoniazid may cause niacin deficiency by inhibiting niacin incorporation into nicotinamide adenine dinucleotide.

Isoniazid is an inhibitor of monoamine oxidase (MAO) and diamine oxidase (DAO), therefore can reduce tyramine and histamine metabolism, causing symptoms such as headache, sweating, palpitations, flushing, and hypotension. Patients should be advised against ingesting foods rich in tyramine and/or histamine during treatment with isoniazid, such as cured meat, some cheeses (e.g. matured cheeses), wine, beer and some fish (e.g. tuna, mackerel, salmon).

4.6. Fertility, pregnancy and lactation

Pregnancy:

Isoniazid crosses the placenta. Therefore, isoniazid should only be used in pregnant women or in women of child-bearing potential if the potential benefit justifies the potential risk to the foetus. It is considered that untreated tuberculosis represents a far greater hazard to a pregnant woman and her foetus than does treatment of the disease. Pyridoxine supplementation is recommended.

Breast-feeding:

Isoniazid passes into breast milk. When administered to nursing mother, breast-fed infants should be monitored for possible signs of isoniazid toxicity. Administration of pyridoxine to the breast-feeding mother and infant may be considered.

4.7. Effects on ability to drive and use machines

Isoniazid has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

Undesirable effects are listed by MedDRA System Organ Classes.

Assessment of undesirable effects is based on the following frequency groupings:

Very common: ≥ 1/10

Common: ≥ 1/100 to <1/10

Uncommon: ≥ 1/1,000 to <1/100

Rare: ≥ 1/10,000 to <1/1,000

Very rare: <1/10,000

Frequency not known: cannot be estimated from the available data.

Blood & lymphatic system disorders

Frequency not known

Haemolytic and aplastic anaemias, agranulocytosis,

Immune system disorders

Frequency not known

Hypersensitivity reactions including various types of skin eruptions, fever, lymphadenopathy,

Metabolism & Nutrition disorders

Frequency not known

Hyperglycaemia, Hypoglycaemia, metabolic acidosis, pellagra (nicotinic acid deficiency). Nicotinic acid deficiency may be related to an isoniazid-induced pyridoxine deficiency which affects the conversion of tryptophan to nicotinic acid.

Psychiatric disorders

Frequency not known

Psychotic disorder; euphoria. Although isoniazid usually has a mood elevating effect, mental disturbances, ranging from minor personality changes to major mental derangement have been reported; these are usually reversed on withdrawal of the drug

Nervous disorders

Frequency not known

Peripheral neuropathy; seizure; Hyperreflexia may be troublesome with doses of 10mg per kg body weight, Optic neuritis

Eye disorders

Rare

Optic atrophy

Musculoskeletal and connective tissue disorders

Frequency not known

Systemic lupus erythematosus, lupus-like syndrome

General disorders and administration site conditions

Frequency not known

Pyrexia

Ear & labyrinth disorders

Frequency not known

Deafness; tinnitus; vertigo. These have been reported in patients with end stage renal impairment

Vertigo may be troublesome with doses of 10mg per kg body weight

Respiratory, thoracic & Mediastinal disorders

Frequency not known

Interstitial lung disease

Gastrointestinal disorders

Frequency not known

Nausea, vomiting, constipation, dry mouth, pancreatitis and other gastrointestinal effects

Hepatobiliary disorders

Frequency not known

Acute hepatic failure, Liver injury, Jaundice

The risk of these undesirable effects increases with age, especially over the age of 35; it may be serious and sometimes fatal with the development of necrosis.

Uncommon

Hepatitis

Skin and subcutaneous tissue disorders

Frequency not known

Erythema multiforme, Stevens-Johnson syndrome.

Rare

Toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS).

Renal & urinary disorders

Frequency not known

Dysuria

Reproductive system & breast disorders

Frequency not known

Gynaecomastia

Vascular disorders

Frequency not known

Vasculitis

Investigations

Frequency not known

Hepatic enzyme increased

Withdrawal symptoms, which may occur on the cessation of the treatment, include headache, insomnia, excessive dreaming, irritability and nervousness.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms of overdose with isoniazid are slurred speech, metabolic acidosis, hyperglycaemia, hallucinations, respiratory and central nervous system depression, nausea, vertigo, convulsions and coma.

Treatment of overdosage may include gastric lavage following intubation and the control of convulsions by anti-convulsants given intravenously as well as the intravenous injection of large doses of pyridoxine. Metabolic acidosis is corrected with sodium bicarbonate. Forced diuresis may be tried and haemodialysis or peritoneal dialysis has been used.